PHR 338 Lecture Notes - Lecture 8: Wolters Kluwer, Pharmacophore, Intermolecular Force
Page%1%of%9%
%
Medicinal+Chemistry+
Integrated+Pharmacy+2+(PHAR+7602)+
Chemical+Bonds+and+Structure-Activity+Relationships+
%
+
Pre-Class+Assignments+
Study%the%material%guided%by%the%following%reading%objectives.%
+
Reading+Objectives+
1. Become%familiar%with%types%of%drug%targets,%and%their%examples.%
2. Understand%the%chemical%nature%of%proteins,%which%is%the%most%common%type%of%drug%targets.%
3. Understand%the%overall%process%of%receptor-ligand%interaction,%which%includes%forming%of%intermolecular%
interactions,%conformational%changes%to%the%active%site,%signal%transduction,%and%departure%of%the%ligand.%
4. Differentiate%between%the%binding%site%for%an%endogenous%ligand,%and%the%allosteric%binding%site.%
5. Differentiate%between%the%types%of%receptor-ligand%intermolecular%bonds,%and%rank%them%by%their%strength.%
6. Relate%the%impact%of%the%strength%of%intermolecular%bonds%on%the%affinity%for%a%ligand.%
7. Find%how%affinity%is%measured,%and%what%the%dissociation%constant%(Kd)%is.%
8. Relate%the%impact%of%intermolecular%bonds%on%the%induced-fit,%and%how%this%can%affect%the%biological%activity.%
9. Relate%structure-activity%relationship%(SAR)%to%drug-target%interactions.%
10. Differentiate%between%3D%pharmacophore,%and%the%generalized%bond%type%pharmacophore.%
11. Understand%the%similarity%principle%and%how%it%relates%to%identifying%pharmacophores%of%drugs.%
12. Differentiate%between%isosteres,%and%bioisosteres%and%value%their%importance%in%drug%design.%
13. Define%prodrugs%and%appreciate%their%uses%in%improving%the%feature%of%a%drug.%
+
Optional+Reading+References+
1. An% Introduction% to% Medicinal% Chemistry,% 5th%ed.% Graham% Patrick.% Oxford% University% Press.% ISBN:% 978-0-
199697397.%
2. Foye’s%Principles%of%Medicinal%Chemistry,%7th%ed.%Thomas%Lemke%et.%al.%Wolters%Kluwer%Health%ISBN:%978-1-
609133450.%
+
% %
Page%2%of%9%
%
Figure 1: Proteins are the most common type of
drug targets.
%
Figure 2: The 3D structure and function
of proteins (video).
%
Introduction*
In%order%to%design%better%drugs,%we%need%to%understand%how%the%receptors%are%activated%and%how%they%interact%
with%natural%chemical%messengers%(aka,%endogenous%ligands).%Receptor%hypothesis%was%first%developed%by%Ehrlich%
to%explain%the%biologic%action%of%molecular%entities.%He%postulated%that%receptors%are%certain%side%chains%located%
on%the%surfaces%of%cells%and%they%are%complementary%to%chemical%messengers;%the%two%could%therefore%interact%
with%one%another%and%produce%the%biological%action.%To%understand%what%these%side%chains%are%we%will%explain%
the%chemical%nature%of%these%receptors%(aka,%drug%targets),%see%figure%1%below.%
%
%
%
%
%
%
%
%
%
%
%
%
%
%
%
%
%
%
%
%
Since% proteins% are% the% most% common%type% of% drug% targets,% we% will%
have% an% overview% of% at% its% chemical% structure;% watch% the% video% in%
figure%2%by% clicking%on%it.%After%you%watch%the%video,% make% sure%you%
answer% the% following% questions:% What% roles% do% protein% play% in% the%
biological% system?% What% are% the% building% blocks% of% proteins?% What%
are%the%atoms%used%in%these%building%blocks?%What%is%the%difference%
between%primary,%secondary,%tertiary,%and%quaternary%structure%of%a%
protein?%
%
%
%
%
%
%
%
Using%protein%as%an%example%of%a%drug%target,%figure%3%shows%how%a%
drug%(in%orange)%is%interacting%with%the%amino%acids’%side-chains%(in%
blue)% of% a% protein% target% receptor.% The% functional% groups% for% the%
amino% acid% side% chains% of% the% protein% are% interacting% with% the%
functional% groups% of% the% drug.% These% functional% groups% are%
complementary%in% shape% and% are% bonding% to% each% other% by%
Page%3%of%9%
%
intermolecular%bonds.%Types%of%these%bonds%will%be%described%shortly%in%later%on.%
%
The*Overall*Process*of*Receptor-Ligand*Interaction*
The+ binding+ site%is% a% hydrophobic%hollow% on% receptor’s% surface.% It% is% nearly% the% correct% shape%for% the% natural%
chemical%messenger.%The%binding%site%contains%amino%acids,%which%are%recognized%by%the%chemical% messenger.%
Sometimes% a% ligand% might% bind% to% a% location% other% than% the% binding% site% recognized% by% the% messenger,% yet% it%
affects% (positively% or% negatively)% the% activity% of% the% receptor.% This% location% is% called% allosteric%binding% site,% see%
figure%4.%
!
Figure 4: Protein receptor and its binding site (left). A receptor might have an allosteric binding site (right).+
The+ binding+ process%involves% the% binding% site% accepting% and% binding% the% messenger% through% intermolecular%
bonds,% which% results% in% altering% the% shape% of% the% receptor;% i.e.,% “induced% fit”.% Induced% fit% maximizes%
intermolecular% bonding%(optimum% length)% leading% to% further% (domino%like)% effect% known% as% the% signal+
transduction,%which%leads%to%a%chemical%signal%being%received%inside%the%cell%and%producing%the%biological%effect.%
Binding%sites%are%so%specific%that%even%small%changes%in%chemical%structure%of%a%messenger%can%impact%the%binding%
interaction,%and%thus,%the%biological%effect.%Messengers%do%not%enter%the%cell;%they%depart%unchanged%and%are%not%
permanently%bound.%
%
%
%
Figure 5: The binding causes an induced fit, which results in the signal transduction (aka, domino effect), the
messenger then departs the target receptor.
The+binding+interactions%must%be%strong%enough%to%hold%the%messenger%sufficiently%long%for%signal%transduction%
to%take%place,%but%it%must%also%be%weak%enough%to%allow%the%messenger%to%depart.%Therefore,%a%fine%balance%is%
required.% Designing% molecules% with%stronger% binding% interactions%results%in%drugs%that%block%the%binding%site%–%
called%antagonists;%to%be%discussed%later%on.% %
